Aerosol composition comprising formoterol

ABSTRACT

The use of a dry powder comprising (A) formoterol, or a pharmaceutically acceptable salt or solvate thereof, or solvate of said salt, and (B) a pharmaceutically acceptable particulate diluent or carrier in an amount of from 400 μg to 5000 μg per μg of (A) for the preparation of an inhalable medicament for the treatment of chronic obstructive pulmonary disease.

This invention relates to the use of organic compounds in the treatmentof chronic obstructive pulmonary disease (COPD), both reversible andirreversible COPD, reversibility being defined by reference to theeffect of inhalation of a standard dose of a short-acting beta-2 agonistbronchodilator such as salbutamol on the forced expiratory volume in 1second (FEV₁) measured by spirometry. The characteristics of differentstages of COPD are described in the Official Satement of the AmericanThoracic Society (ATS): Am J Respir Crit Care Med Vol 152, pp 577-120,1995, and a Consensus Statement of the European Respiratory society(ERS): European Respiratory Journal 1995, 8, 1398-1420.

It has now surprisingly been found, in accordance with the invention,that formoterol or a pharmaceutically acceptable salt or solvate thereofor solvate of said salt, each hereinafter alternatively referred to asthe formoterol active ingredient, is particularly effective in thetreatment of COPD when administered by inhalation as a dry powder inadmixture with a diluent or carrier in an amount of from 400 μg to 5,000μg per μg of formoterol active ingredient. Administration of such amixture by inhalation to COPD patients facilitates significant sustainedbronchodilation, a very good safety profile, important e.g. for thetreatment of COPD without significant concomitant cardiovasculareffects, and significant improvement in Quality of Life as assessed bythe St George's Respiratory Questionnaire (SGRQ).

Accordingly, the present invention provides, in one aspect, the use of adry powder comprising (A) formoterol, or a pharmaceutically acceptablesalt or solvate thereof, or solvate of said salt, and (B) apharmaceutically acceptable particulate diluent or carrier in an amountof from 400 μg to 5,000 μg per μg of (A) in the preparation of aninhalable medicament for the treatment of chronic obstructive pulmonarydisease.

In a related aspect, the present invention provides a pharmaceuticalcomposition in the form of a dry powder comprising (A) and (B) ashereinbefore defined for use in the treatment of chronic obstructivepulmonary disease.

In another aspect, the present invention provides a method of treatingchronic obstructive pulmonary disease which comprises administering byinhalation to a subject in need of such treatment an effective amount ofa dry powder comprising (A) formoterol, said formoterol being in freeform or in the form of a pharmaceutically acceptable salt or solvatethereof or in the form of a solvate of such a salt, and (B) apharmaceutically acceptable particulate diluent or carrier in an amountof from 400 μg to 5,0000 μg per μg of (A).

In a further aspect, the present invention provides the use of a drypowder comprising (A) formoterol, or a pharmaceutically acceptable saltor solvate thereof, or solvate of said salt, and (B) a pharmaceuticallyacceptable particulate diluent or carrier in an amount of from 400 μg to5,000 μg per μg of (A), said dry powder being substantially free fromfluticasone proprionate, mometasone furoate or tiotropium salts, for thepreparation of an inhalable medicament for the treatment of chronicobstructive pulmonary disease.

The formoterol active ingredient (A) may be in any isomeric form ormixture of isomeric forms, for example a pure enantiomer, particularlythe R,R-enantiomer, a mixture of enantiomers, a racemate or a mixturethereof. Pharmaceutically acceptable salts of formoterol include acidaddition salts with inorganic acids such as hydrochloric acid,hydrobromic acid, sulphuric acid or phosphoric acid, or organic acidssuch as acetic, succinic, glutaric, maleic, fumaric, citric, tartaric,lactic, benzoic, salicylic, p-hydroxybenzoic, p-methoxybenzoic,hydroxynapthoic, methanesulfonic, benzesulfonic, or p-toluenesulfonicacid. Suitable solvates of formoterol and pharmaceutically acceptablesalts thereof include hydrates. A preferred form of formoterol for usein accordance with the invention is formoterol fumarate, especiallyformoterol fumarate dihydrate, conveniently in racemic form. Formoterol,salts and hydrates thereof and salt hydrates thereof as hereinbeforedescribed may be prepared by known methods, for example as described inU.S. Pat. No. 3,994,974 or U.S. Pat. No. 5,684,199.

Accordingly, in a preferred embodiment, the present invention providesthe use of a dry powder consisting, or consisting essentially, of (A)formoterol fumarate dihydrate and (B) a pharmaceutically acceptablediluent or carrier in an amount of from 400 μg to 5,000 μg per μg of (A)for the preparation of an inhalable medicament for the treatment ofchronic obstructive pulmonary disease.

Suitable diluents or carriers include saccharides and/or sugar alcohols,e.g. monosaccharides, disaccharides and polysaccharides such as glucose,arabinose, dextrose, fructose, ribose, mannose, sucrose, trehalose,lactose, maltose or dextran, sugar alcohols such as mannitol andmixtures of two or more thereof. A preferred diluent or carrier islactose, particularly in the form of the monohydrate. The diluent orcarrier is generally present in an amount of 400 to 4000 μg, for example800 to 3000 μg, more preferably 1000 to 2500 μg, especially 2000 to 2500μg, per μg of formoterol active ingredient (A). The mean particlediameter of the formoterol active ingredient (A) is preferably up to 10μm, more preferably up to 5 μm, especially 1 to 5 μm. The diluent orcarrier (B) may be present in the dry powder in the form of particleshaving, for example, a maximum diameter of 300 μm, a preferred maximumbeing 212 μm. The diluent or carrier (B) may conveniently have a medianparticle diameter of 40 to 100 μm, e.g. 50 to 75 μm. The particle sizeof the formoterol active ingredient (A), and that of the diluent orcarrier (B), can be reduced to the desired level by conventionalmethods, for example by grinding in an air-jet mill, ball mill orvibrator mill, by sieving, by microprecipitation, by spray-drying, bylyophilisation or by recrystallisation from supercritical media.

In a preferred embodiment of the invention, the dry powder is in acapsule, usually of a pharmaceutically acceptable natural or syntheticpolymer such as gelatin or hydroxypropyl methylcellulose, the capsulecontaining a unit dose of formoterol active ingredient (A). Doses offormoterol active ingredient (A) to be inhaled in accordance with theinvention may be, in general, from 1 μg to 60 μg. When (A) is formoterolfumarate dihydrate, the dose may be, for example, from 6 μg to 48 μg.Preferred doses are from 6 μg to 36 μg, for example 6 μg, 12 μg, 18 μg,24 μg, 30 μg, or 36 μg, the 12 μg and 24 μg being especially preferredand the 12 μg dose the most preferred. These doses may be administeredonce or twice daily, preferably twice daily, the preferred maximum dailydose being 48 μg. For on demand usage, the 6 μg or 12 μg dose ispreferred, being inhaled as needed in accordance with a preferredmaximum daily dose of 48 μg. When the dry powder is in a capsulecontaining a unit dose of (A), e.g. 6 μg, 12 μg or 24 μg of (A), theamount of diluent/carrier is preferably such as to bring the totalweight of dry powder per capsule to between 5 mg and 25 mg, e.g. to 5mg, 10 mg, 15 mg, 20 mg or, especially, 25 mg.

In especially preferred embodiements the dry powder is in a capsule, thecapsule containing 12 μg of formoterol active ingredient (A) and 4988 μgto 49988 μg, for example 4988 μg or 9988 μg or 14988 μg, more preferably19988 μg to 24988 μg, for example 19988 μg or, especially, 24988 μg ofdiluent or carrier (B).

As will be understood by those skilled in the art, a dry powdercontained in a capsule may be inhaled by inserting the capsule in a drypowder inhalation device adapted to pierce a capsule containing the drypowder on actuating the device, thereby releasing the dry powder forinhalation by the user—a dry powder capsule inhaler. Such devices arewell known in the art and are commercially available. For example, asuitable inhalation device is described in U.S. Pat. No. 3,991,761,which is incorporated herein by reference, particularly as described inthe claims of U.S. Pat. No. 3,991,761 and as described with reference tothe drawings of U.S. Pat. No. 3,991,761; this device may be modified bycoating the capsule-piercing pins with a polymer, as described inWO99/45987. A preferred inhalation device is one adapted to receive asingle capsule containing the dry powder, i.e. a single capsule inhaler,for example the commercially available Aerolizer® inhaler.

In another preferred embodiment of the invention, the dry powder may bein a reservoir of a multi-dose dry powder inhaler adapted to deliver aunit dose, for example 5 μg, 6 μg, 9 μg, 10 μg, 12 μg, 15 μg, 18 μg, 20μg, 24 μg, 25 μg, 30 μg or 36 μg, preferably from 5 to 15 μg offormoterol active ingredient (A), particularly formoterol fumaratedihydrate, per actuation, for example from a powder having a formoterolfumarate dihydrate:lactose weight ratio of 5:4995, 5:9995, 5:14995,10:4990, 10:9990, 10:14990, 12:4988, 12:9988 12:14998, 15:9985 or15:14985. Multi-dose dry powder inhalers are well known in the art andare commercially available. For example, a suitable multi-dose inhaleris that described in WO97/20589.

Treatment of COPD in accordance with the invention includes treatment ofreversible or irreversible, mild, moderate or severe COPD (includingchronic bronchitis and emphysema) and conditions associated therewith,e.g. bronchospasm, loss of lung function, loss of exercise capacity,breathlessness, dyspnea or loss of lung elasticity. Thus treatment ofCOPD in accordance with the invention includes maintenance(prophylactic) treatment or on-demand or rescue treatment ofbronchospasm associated with COPD, treatment to slow progressive loss oflung function, treatment to improve exercise capacity, and treatment toimprove Quality to Life according to the SGRQ.

The effect of compositions of the invention in the treatment of COPD canbe monitored in a conventional manner, e.g. by determining parameterssuch as forced expiratory volume in 1 second (FEV₁), vital capacity(VC), forced vital capacity (FVC), Quality of Life, peak expiratory flow(PEF), exercise capacity (e.g. Shuttle Walking Test) and lung compliance(CL) at intervals during treatment. Quality of Life may be measuredaccording to the SGRQ (P. W. Jones et al., Respir Med. 1991; 85 (SupplB): 25-31).

The invention is illustrated by the following Examples.

EXAMPLE 1

Gelatin capsules suitable for use in a capsule inhaler are prepared,each capsule containing a dry powder consisting of 6 μg of formoterolfumarate dihydrate which has been ground to a mean particle diameter of1-5 μm in an air jet mill and 4994 μg of lactose monohydrate having aparticle diameter of below 212 μm. These capsules are used in thetreatment of COPD patients by inserting a capsule into the capsulechamber of the inhaler described in U.S. Pat. No. 3,991,761 andactuating the piercing devices to perforate the capsule and release thedry powder when air is inhaled through the capsule chamber by a patient.

EXAMPLES 2-29

Example 1 is repeated using the amounts of the formoterol fumaratedihydrate and the lactose monohydrate shown in the table below in placeof the amounts used in that Example:

Formoterol Fumarate Example Dihydrate (μg) Lactose Monohydrate (μg) 2 69994 3 6 14994 4 6 19994 5 6 24994 6 12 4988 7 12 9988 8 12 14988 9 1219988 10 12 24988 11 12 29988 12 18 9982 13 18 14982 14 18 19982 15 1824982 16 18 29982 17 24 9976 18 24 14976 19 24 19976 20 24 24976 21 2429976 22 30 14970 23 30 19970 24 30 24970 25 30 29970 26 36 14964 27 3619964 28 36 24964 29 36 29964

EXAMPLE 30

Two groups of patients suffering from COPD are treated with formoterol.One group has reversible COPD, showing at least 15% increase in FEV₁ 30minutes after inhaling 200 μg of salbutamol. The other group hasirreversible COPD, showing less than 15% increase in FEV₁ 30 minutesafter inhaling 200 μg of salbutamol. Both groups are treated byinhalation twice daily for 12 weeks from a capsule containing a drypowder consisting of 12 μg of formoterol fumarate dihydrate having amean particle diameter of 1 to 5 μm and 24988 μg of lactose monohydratehaving a particle diameter below 212 μm, using an Aerolizer® inhaler.After treatment for 12 weeks, the patients' lung function (FEV₁) ismeasured at intervals for 12 hours after dosing, the measured FEV₁ isplotted against time after dosing and the area under the curve (AUC) ofthe resulting plot is determined.

1. A method of treating chronic obstructive pulmonary disease consistingessentially of administering by inhalation to a subject in need of suchtreatment an effective amount of a dry powder comprising (A) formoterol,or a pharmaceutically acceptable salt or solvate thereof, or solvate orsaid salt, and (B) a pharmaceutically acceptable particulate diluent orcarrier in an amount of 400 μg to 5,000 μg per μg of (A), wherein saidpharmaceutically acceptable diluent or carrier has a median particlediameter of 40 to 100 μm, and said formoterol is the only activeingredient.
 2. A method according to claim 1, in which the formoterol(A) is in the form of formoterol fumarate dihydrate.
 3. A method oftreating chronic obstructive pulmonary disease which comprisesadministering by inhalation to a subject in need of such treatment aneffective amount of a dry powder consisting, or consisting essentially,of (A) formoterol fumarate dihydrate and (B) a pharmaceuticallyacceptable diluent or carrier in an amount from 400 μg to 5,000 μg perμg of (A), wherein said pharmaceutically acceptable diluent or carrierhas a median particle diameter of 40 to 100 μm.
 4. A method according toclaim 3, in which the diluent or carrier (B) is a saccharide, a sugaralcohol or a mixture thereof.
 5. A method according to claim 4, in whichthe diluent or carrier (B) is lactose.
 6. A method according to claim 3,in which the diluent or carrier (B) is present in an amount of 800 to3000 μg per μg of (A).
 7. A method according to claim 3, in which themean particle diameter of (A) is up to 10 μm.
 8. A method according toclaim 3, in which the dry powder is in a capsule, the capsule containinga unit dose of (A).
 9. A method according to claim 8, in which thecapsule contains 12 μg of (A) and 19988-24988 μg of diluent or carrier(B).
 10. A method according to claim 3, in which the dry powder is in areservoir of a multi-dose powder inhaler adapted to deliver a unit doseof (A) per actuation.